Background

Paraneoplastic syndromes are a group of rare disorders that are triggered by an abnormal immune system response to an underlying (usually undetected) malignant tumor. Patients with paraneoplastic neurological syndrome (PNS) most often present with neurologic symptoms before an underlying tumor is detected.

Paraneoplastic neurologic syndromes include many neurologic disorders including paraneoplastic cerebellar degeneration (PCD) caused by an immune-mediated mechanism other than a metastatic complication in patients with an underlying malignancy. Any part of the nervous system can be involved depending on the type of primary malignancy. These syndromes affect 1-3% of all cancer patients.
[1] These syndromes are difficult to diagnose and respond poorly to treatment. However, the oncologic outcome of patients with antibody-associated paraneoplastic syndromes does not significantly differ from that of patients who do not have the antibodies or a paraneoplastic syndrome.

Paraneoplastic cerebellar degeneration is a rare nonmetastatic complication of a carcinoma, typically mediated by antibodies generated against tumor antigens (proteins). Similar proteins are also expressed on Purinje cells and possibly other cells within the cerebellum. The cancer-fighting antibodies mistakenly attack these normal protein cells in the cerebellum. This immune activation in the central nervous system (CNS) results in cerebellar injury and dysfunction defined as paraneoplastic cerebellar degeneration.

An association between paraneoplastic cerebellar degeneration and occult gynecologic cancers (breast or ovarian) was first identified in 1938, and the syndrome was described fully by Brain in 1951.
[2] Posner found that patients with paraneoplastic cerebellar degeneration can be classified according to the presence or absence of an antibody that reacted with an antigen present in both the tumors and in cerebellar Purkinje neurons obtained from these patients.
[3]

Paraneoplastic cerebellar degeneration is a syndrome that occurs predominantly in patients with cancer of the ovary, uterus, or adnexa; cancer of the breast; small-cell carcinoma of the lung; or Hodgkin lymphoma.
[4, 5]

The onset of symptoms of cerebellar degeneration indicates the presence of an occult malignancy. Not all gynecologic cancers present as paraneoplastic neurologic syndrome; however, in a clinical presentation consistent with a paraneoplastic neurologic syndrome, the chances of underlying malignancy are very high.

The image below illustrates the workup of paraneoplastic cerebellar degeneration.

Pathophysiology

Paraneoplastic cerebellar degeneration is caused by the secondary effects of cancer and is believed to be immune mediated. High titers in the patient's serum and cerebrospinal fluid (CSF) of autoantibodies directed against both neurons and tumor have been detected in some forms of this syndrome.
[6, 7] These autoantibodies are considered the result of an immunologic response to tumor and may cross-react with cells of the nervous system, causing neuronal damage.

Specific forms of this syndrome often are associated with specific antineuronal antibodies and tumors. The onset of neurologic symptoms and detection of these antibodies precede diagnosis of the tumor more 60% of the time. Therefore, detection of these antibodies greatly assists the diagnosis of this syndrome and prompts investigations for the underlying tumor. Not all patients presenting with paraneoplastic cerebellar degeneration and its clinical features have recognizable antineuronal antibodies. However, this does not exclude the likelihood of occult malignancy.
[8, 9] In approximately 40% of patients, no antibodies are identified.

The Yo antigen is a cytoplasmic protein (CDR2) that interacts with c-Myc. CDR2 is expressed mostly on the Purkinje cells of the cerebellum and can also be present in neurons of the brain stem. Studies suggest that CDR2 sequesters c-Myc in the neuronal cytoplasm and downregulates its activity. Disruption of this interaction by anti-Yo antibodies may increase c-Myc activity, leading to apoptosis of the Purkinje cells.
[10, 11]

Antibodies could therefore play an initial pathogenic role in paraneoplastic cerebellar degeneration, although the T-cell immune response is believed to be the major effector of neuronal degeneration. In most of these syndromes, the antigens have been identified and the genes have been cloned.

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Epidemiology

Frequency

United States

In one study, paraneoplastic cerebellar degeneration was observed in 25% of paraneoplastic neurologic syndromes, occurring in 2 of every 1000 patients with cancer.
[12]

Mortality/Morbidity

In the study cited above, median survival duration was 100 months for patients with breast cancer and 22 months for those with gynecologic cancer. Although paraneoplastic cerebellar degeneration led to the diagnosis of cancer in 63% of patients, cancer progression was the cause of death in 52%.
[12]

Sex

Both sexes are affected, but paraneoplastic cerebellar degeneration is far more common in women than in men.

Age

See the list below:

Paraneoplastic cerebellar degeneration associated with anti-Yo antibody occurs in middle-aged women with occult ovarian or breast cancer that is usually indolent.

Paraneoplastic cerebellar degeneration associated with anti-Hu antibody occurs in middle-aged men and women or patients with risk factors for lung cancer.

When the condition is associated with Hodgkin lymphoma, patients are usually young men, and the cerebellar disease often follows the diagnosis of lymphoma.

MRI of a 29-year-old female with ARCA1. Sagittal T1 shows marked diffuse cerebellar atrophy with no atrophy of the cerebral cortex, midbrain, pons, or medulla. Image from National Institutes of Health.

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: SK<br/>Serve(d) as a speaker or a member of a speakers bureau for: Eisai, Lundbeck, Sunovion, Supernus, UCB.